An individual woman's susceptibility to breast cancer is determined by her inherited genetic susceptibility and her personal environment as well as interactions between and within genes and environmental factors. The environment is also complex, consisting of both endogenous and exogenous factors. Importantly, in breast cancer, the susceptibility to environmental agents is highly dependent on the physiological and developmental status of the breast at the time of exposure, i.e., windows of susceptibility. Several major hormonal landmarks in a woman's life impact on the breast's developmental status and modulate susceptibility. This proposal will focus on three post-natal windows of breast cancer susceptibility using both rat and human studies. In rats, these windows include the """"""""immature"""""""" window (3 week old rats) corresponding to childhood in humans, the """"""""adolescent"""""""" window (7 week old rats), and the novel """"""""older adult"""""""" window (65 week old rats) corresponding to peri- menopause in women. It is hypothesized that susceptibility to environmental induced breast cancer is modulated by window-specific risk alleles/genes. Results obtained from these rat models will be extended to women using a comparative genomics approach focusing on genetic epidemiological investigations.
Aim 1 will determine if seven previously identified mammary carcinoma susceptibility (Mcs) alleles that have been shown to modulate mammary cancer risk at the adolescent window are unique for this window or will also function at the immature or older adult windows.
Aim 2 a will phenotype mammary gland at all three windows by integrating gland morphology with global gene expression.
Aims 2 b and 2c will ask if mammary carcinomas induced by exposure at different windows show window-specific patterns of gene expression and pathway signaling. These expression patterns will be compared to human breast cancer gene expression patterns.
Aim 3 will extend work on previous aims by genetically identifying unique quantitative risk loci (QTL) that are not active at the adolescent window but modulate risk at the other two windows.
Aim 4 will focus on a comparative genomics/molecular epidemiologic case-control study of over 7,000 women to identify established and suspected GWAS SNPs in human regions homologous to our loci (Aim 1) and QTL (Aim 3). Importantly, all major study planning will include input from partners affiliated with several advocacy and community groups within Wisconsin (Aim 5). Advocates and scientists will jointly communicate important results from these studies as well as studies from other BCERP collaborators.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01ES019466-04
Application #
8462270
Study Section
Special Emphasis Panel (ZES1-LKB-V (02))
Program Officer
Reinlib, Leslie J
Project Start
2010-09-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$432,224
Indirect Cost
$141,164
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Zumwalde, Nicholas A; Haag, Jill D; Sharma, Deepak et al. (2016) Analysis of Immune Cells from Human Mammary Ductal Epithelial Organoids Reveals Vδ2+ T Cells That Efficiently Target Breast Carcinoma Cells in the Presence of Bisphosphonate. Cancer Prev Res (Phila) 9:305-16
Henning, Amanda N; Haag, Jill D; Smits, Bart M G et al. (2016) The Non-coding Mammary Carcinoma Susceptibility Locus, Mcs5c, Regulates Pappa Expression via Age-Specific Chromatin Folding and Allele-Dependent DNA Methylation. PLoS Genet 12:e1006261
Smits, Bart M G; Haag, Jill D; Rissman, Anna I et al. (2013) The gene desert mammary carcinoma susceptibility locus Mcs1a regulates Nr2f1 modifying mammary epithelial cell differentiation and proliferation. PLoS Genet 9:e1003549
Sharma, Deepak; Eichelberg, Mark R; Haag, Jill D et al. (2012) Effective flow cytometric phenotyping of cells using minimal amounts of antibody. Biotechniques 53:57-60
Pirone, Jason R; D'Arcy, Monica; Stewart, Delisha A et al. (2012) Age-associated gene expression in normal breast tissue mirrors qualitative age-at-incidence patterns for breast cancer. Cancer Epidemiol Biomarkers Prev 21:1735-44
Sharma, Deepak; Smits, Bart M G; Eichelberg, Mark R et al. (2011) Quantification of epithelial cell differentiation in mammary glands and carcinomas from DMBA- and MNU-exposed rats. PLoS One 6:e26145